Association of tumor necrosis factor receptor type II polymorphism 196R with Systemic lupus erythematosus in the Japanese: molecular and functional analysis.

OBJECTIVE: To investigate whether a polymorphism(s) or mutation(s) in the tumor necrosis factor receptor II (TNFRII) gene is involved in the pathogenesis of systemic lupus erythematosus (SLE). METHODS: All 10 exons of the TNFRII gene were analyzed by exon-specific polymerase chain reaction-single-strand conformation polymorphism, followed by nucleotide sequencing of exons that displayed aberrant bands. To analyze the function of the TNFRII polymorphisms, the full-length TNFRII complementary DNA of each allele was transfected in HeLa cells and then studied for specific binding of 125I-TNFalpha, as well as interleukin-6 (IL-6) production and cytotoxic activity after treatment with recombinant human TNFalpha. RESULTS: We identified 4 polymorphisms, at codons 56, 181, 196, and 232. The latter 2 had amino acid substitutions M196R and E232K, respectively. Only the 196R allele was significantly associated with SLE in our 105 Japanese SLE patients, with an allele frequency of 20.5%, compared with 12.6% in 99 healthy controls (P = 0.0335). More importantly, using TNFRII-transfected HeLa cells, we demonstrated significantly increased IL-6 production by 196R TNFRII compared with 196M TNFRII. The cytotoxic activity induced by 196R TNFRII was also increased compared with that of 196M TNFRII. This increase was achieved without affecting the binding affinity of TNFalpha to TNF-RII, as demonstrated by the finding that specific TNFalpha binding to the HeLa transfectants of 196R and 196M TNFRII was similar, with Kd values of 3.12 x 10(-10)M and 4.34 x 10(-10)M, respectively. CONCLUSION: These results suggest that 196R TNFRII, which transduces the signals of TNFalpha more effectively than does 196M TNFRII, is involved in the pathogenesis of SLE.     

Fc gamma receptor II polymorphism in Vietnamese patients with systemic lupus erythematosus

The polymorphism of the Fc receptor for IgG class IIA (Fc gammaRIIA) in Vietnamese patients with systemic lupus erythematosus (SLE) was examined by using the polymerase chain reaction (PCR) method with genomic DNA and allele-specific primers. In the frequency of Fc gammaRIIA genotypes, the homozygosity of Fc gammaRIIA-H131 was four (8.3%) of 48 SLE patients and 16 (37.2%) of 43 healthy controls (P < 0.01). The allele frequency of Fc gammaRIIA-H131 in SLE patients was also significantly lower than that in the controls (P < 0.05). The unusual distribution of Fc gammaRIIA polymorphism suggested that Fc gammaRIIA might be involved in the development of SLE in Vietnamese patients.     

The biallelic variable number of tandem repeats of the tumor necrosis factor receptor 2 promoter in systemic lupus erythematosus

The objective of this study was to investigate whether the variable number of tandem repeats (VNTR) of the tumor necrosis factor receptor 2 (TNFR2) promoter is associated with susceptibility to systemic lupus erythematosus (SLE) and its clinical phenotypes. A biallelic VNTR within a 42-bp region in the TNFR2 gene promoter was determined by polymerase chain reaction in 88 SLE patients and 95 healthy control subjects. Clinical manifestations were analyzed in each patient and correlated with the genotypes. When the TNFR2 promoter VNTR was compared between Korean and Caucasian healthy controls with respect to allele frequencies, there was a significant difference (alleles 1 and 2: 39, 151 in Koreans vs 60, 138 in Caucasians, respectively; chi-squared test 4.38; 2 df; P=0.036). The genotype distribution of the TNFR2 promoter VNTR did not differ between SLE patients and control subjects (1.1, 1.2, and 2.2 genotypes 7, 14, 67 vs 5, 29, and 61 controls, respectively; chi-squared test 5.19; 2 df; P=0.061). According to the TNFR2 promoter genotypes in the lupus patients, clinically there was no significant difference in age at onset, anti-dsDNA titer, C4 level, systemic lupus erythematosus disease activity index (SLEDAI), Systemic Lupus International Collaborating Clinics/American College of Rheumatology (SLICC/ACR) damage index, or autoantibodies. However, the 1.1 genotype group showed the lowest C3 level and more frequent renal involvement than the 1.2 and 2.2 genotype groups. In conclusion, an ethnic difference in the TNFR2 promoter VNTR has been found and the biallelic VNTR of the TNFR2 promoter may be associated with clinical phenotypes in SLE.     

The association of −627 interleukin-10 promoter polymorphism in Chinese patients with systemic lupus erythematosus

The objective of the study is to examine whether interleukin-10 (IL-10) promoter polymorphism is a marker of susceptibility of systemic lupus erythematosus (SLE) in Chinese patients in Taiwan. The study included 119 Chinese patients with SLE. One hundred unrelated healthy individuals living in central Taiwan served as control subjects. Each polymorphism was detected as a result of a polymerase chain reaction (PCR)-based restriction analysis. The PCR product length was determined to be 412 bp (CC) whereas two fragments of 236 and 176 bp were determined to be excisable lengths (AA). The relationship between the IL-10 gene polymorphism and clinical manifestations of SLE was evaluated. For the genotype and allelic frequency, there were statistically significant differences between the SLE patients and the normal control subjects (p=0.007 and 0.003, respectively). But we did not detect any association of carriage rate of the IL-10 polymorphism and the normal control subjects (p=0.077). Furthermore, we did not detect any association of IL-10 genotype with antinuclear antibody, malar rash, photosensitivity, discoid lupus, mucosal ulcer, arthritis, serositis, hematology, immunology, involvement of central nervous system, and renal disease involvement in the SLE patients. The significant relation of −627 IL-10 genotype and allelic frequency with SLE implies that the IL-10 gene polymorphism can serve as a candidate gene marker for further study in patients with SLE in Taiwan.     

Polymorphisms in the promoter region of RANTES and the regulatory region of monocyte chemoattractant protein-1 among Chinese children with systemic lupus erythematosus

OBJECTIVE: Chemokines play an important role in the physiology and pathophysiology of acute and chronic inflammatory processes. We investigated whether chemokines such as RANTES (regulated upon activation, normally T cell expressed and secreted) promoter and monocyte chemoattractant protein-1 (MCP-1) regulatory polymorphisms were associated with systemic lupus erythematosus (SLE) in Chinese children. METHODS: Forty-six patients with SLE and 107 healthy children of comparable ages were studied for genotypes with polymerase chain reaction-based assays. RESULTS: The frequency and distribution of genotypes of the -28(C/G) RANTES gene polymorphism were significantly different between the 2 groups (p < 0.001), and the RANTES -28G allele was significantly more frequent in patients with SLE than in healthy controls (23.9% vs 11%; p = 0.006, OR 2.37, 95% CI 1.25-4.28). There was no significant difference in the frequency or in the distribution of genotypes of the -2518(A/G) MCP-1 and the -403(G/A) RANTES gene polymorphisms between patients and controls (p = 0.32 and p = 0.19, respectively). The RANTES -28G allele was also significantly associated with higher initial levels of antinuclear antibody, lower levels of C3, and higher incidences of central nervous system lupus. CONCLUSION: In the Chinese population, children with RANTES -28C/G polymorphisms have increased risk of developing SLE. Healthy controls with the C/G or G/G genotype were 2.37 times more likely to have SLE compared to those with the C/C genotype.     

Interleukin-6 promoter polymorphism −174 G/C is associated with nephritis in Portuguese Caucasian systemic lupus erythematosus patients

Interleukin-6 (IL-6) is a multifunctional cytokine with an important pathophysiological role in systemic lupus erythematosus (SLE). The polymorphism of the IL-6 gene promoter at position −174, which appears to influence the production of this cytokine, has been associated with susceptibility to some rheumatic diseases. The aim of this study is to investigate whether the IL-6 −174 G/C polymorphism associates with lupus susceptibility or affects disease characteristics in Portuguese patients with SLE. The association between −174 G/C and lupus diagnosis was studied in 115 adult SLE patients (95.7% females) and 152 healthy controls (94.7% females), all Caucasians. There were no significant differences in genotype or allele frequency between patients and controls. The −174 C/C genotype was independently associated with renal disease and the C allele with the presence of irreversible damage. The IL-6 gene promoter polymorphism at position −174 does not contribute to SLE susceptibility in Portuguese Caucasian patients but may predispose to specific manifestations of the disease.     

Can tumor necrosis factor receptor II gene 676T>G polymorphism predict the response grading to anti-TNFα therapy in rheumatoid arthritis?

In this study we analyzed whether the polymorphisms 676T>G in the tumor necrosis factor receptor (TNFR) II gene and -308G>A in the TNFalpha promoter gene may influence the response grading to anti-TNFalpha therapy in rheumatoid arthritis. We enrolled and genotyped 105 RA patients treated with etanercept (n = 55), infliximab (n = 40) and adalimumab (n = 10) for 1 year. The clinical response was evaluated according to the ACR criteria every 3 months. Patients with TNFRII 676TG genotype was significantly associated with lower ACR response compared with 676TT genotype, at 3 (OR 3.78 95% CI 1.07-13.31) and 12 months (OR 4.30 95% CI 1.16-15.99) of treatment. No significant association between TNFalpha -308G>A polymorphism and the clinical response was found. TNFRII 676TG genotype is associated with a lower response to anti-TNFalpha therapy, independently from the specific agent used. This polymorphism could become a useful genetic marker for predicting the different response grading to anti-TNFalpha therapy.     

Association of tumor necrosis factor receptor type II polymorphism 196R with systemic lupus erythematosus in the Japanese: Molecular and functional analysis

Objective

To investigate whether a polymorphism(s) or mutation(s) in the tumor necrosis factor receptor II (TNFRII) gene is involved in the pathogenesis of systemic lupus erythematosus (SLE).

Methods

All 10 exons of the TNFRII gene were analyzed by exon‐specific polymerase chain reaction–single‐strand conformation polymorphism, followed by nucleotide sequencing of exons that displayed aberrant bands. To analyze the function of the TNFRII polymorphisms, the full‐length TNFRII complementary DNA of each allele was transfected in HeLa cells and then studied for specific binding of ¹²⁵I‐TNFα, as well as interleukin‐6 (IL‐6) production and cytotoxic activity after treatment with recombinant human TNFα.

Results

We identified 4 polymorphisms, at codons 56, 181, 196, and 232. The latter 2 had amino acid substitutions M196R and E232K, respectively. Only the 196R allele was significantly associated with SLE in our 105 Japanese SLE patients, with an allele frequency of 20.5%, compared with 12.6% in 99 healthy controls (P = 0.0335). More importantly, using TNFRII‐transfected HeLa cells, we demonstrated significantly increased IL‐6 production by 196R TNFRII compared with 196M TNFRII. The cytotoxic activity induced by 196R TNFRII was also increased compared with that of 196M TNFRII. This increase was achieved without affecting the binding affinity of TNFα to TNFRII, as demonstrated by the finding that specific TNFα binding to the HeLa transfectants of 196R and 196M TNFRII was similar, with K_d values of 3.12 × 10⁻¹⁰M and 4.34 × 10⁻¹⁰M, respectively.

Conclusion

These results suggest that 196R TNFRII, which transduces the signals of TNFα more effectively than does 196M TNFRII, is involved in the pathogenesis of SLE.

     

Clinical significance of serum TNFα and -308 G/A promoter polymorphism and serum Il-6 and -174 G/C promoter polymorphism in systemic lupus erythematosus patients

IntroductionSystemic lupus erythematosus (SLE) is a disorder of immune regulation where cytokine imbalance and genetic factors are implicated in its pathogenesis.Aim of the workTo evaluate the clinical significance of serum levels of tumor necrosis factor alpha (TNFα) and its -308 G/A promoter polymorphism as well as the IL-6 and -174 promoter polymorphism in SLE patients and find any association to the clinical and laboratory features as well as to the disease activity and severity.Patients and methodsWe studied 37 female SLE patients and age and gender matched healthy control. Demographic, clinical and serological data were evaluated and the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) and the Systemic Lupus International Collaboration Clinics/ACR Damage Index (SLICC) were assessed. Serum TNF-α and IL-6 levels were measured using enzyme-linked immunosorbent assay (ELISA) and DNA genotyped for TNF-α promoter (-308 G/A) and IL-6 promoter (-174 G/C) by polymerase-chain reaction-restriction fragment-length polymorphism (PCR-RFLP) analysis.ResultsSerum TNF-α and IL-6 levels were significantly higher in the SLE patients compared to control. Regarding IL-6, there was a statistically significant difference between the levels in the three groups according to the promoter polymorphisms. Patients with constitutional symptoms showed higher level of IL-6 while the TNF-α level was significantly lower in those with pulmonary manifestations. There was a tendency to a higher TNF-α and IL-6 level in those with neuropsychiatric manifestations.ConclusionSerum TNF-α, -308 G/A promoter polymorphism, IL-6 and -174 G/C were higher in SLE patients than in healthy controls. To confirm our results we propose that larger scale, multicenter studies with longer evaluation periods are needed.     

Systemic lupus erythematosus candidate genes in the Italian population: evidence for a significant association with interleukin-10

OBJECTIVE: To determine whether 7 candidate genes, including tumor necrosis factor receptor II, bcl-2, CTLA-4, interleukin-10 (IL-10), CD19, Fcy receptor type IIA (CD32), and IL-1 receptor antagonist, may contribute to susceptibility to systemic lupus erythematosus (SLE) in the Italian population. METHODS: The association with SLE of intragenic markers for each candidate gene, including either microsatellites or dimorphisms, was analyzed. Gene frequencies of these gene markers were compared for patients and ethnically matched controls. Significance was tested by chi-square test on 2 x 2 tables and by Monte Carlo simulation on 2 x N tables. RESULTS: A significant increase was found in SLE patients (0.170 versus 0.095; chi2y = 4.11, P = 0.0425) in the frequency of the 140-basepair allele of the IL10.G microsatellite located in the promoter region of the IL-10 gene. This finding was confirmed in a second independent panel where, again, the frequency of the 140-bp allele was found to be significantly increased in SLE patients versus controls (0.176 versus 0.086; chi2y = 3.95, P = 0.0470). Considering the 2 panels together, the relative risk conferred by the presence of the 140-bp allele was 1.78 (95% confidence interval 1.19-2.66). Conversely, no significant association was detected for the remaining 6 candidate genes, even when the patients were stratified according to the presence of different clinical and immunologic features according to the presence of the associated HLA-DR or IL-10 alleles. CONCLUSION: Of the 7 candidate genes tested, only IL-10 was significantly associated with SLE in Italian patients. This genetic marker represents, apart from HLA, the only genetic susceptibility factor for SLE found so far in the Italian population.     

几种趋化性细胞因子及受体基因多态性与系统性红斑狼疮的关联研究

目的探讨基质衍生因子1-3'A(stromalcell-derivedfactor1-3'A,SDF1-3'A)、趋化性细胞因子受体2-64I(chemoattractantcellreceptor2-64I,CCR2-64I)190位点、单核趋化蛋白1(monocytechemoattractantprotein-1promoter-2518polymorphism,-2518MCP-1)基因多态性及其交互作用与系统性红斑狼疮(SLE)的相关性。方法以143例SLE病人和157名健康对照为对象进行病例对照研究。应用聚合酶链反应—限制性内切酶片段长度多态性(polymerasechainreaction/restrictionfragmentlengthpolymor-phism,PCR-RFLP)方法确定SDF1-3'A和-2518MCP-1基因多态性,应用突变特异性扩增系统(amplifica-tionrefractorymutationsystem,ARMS)确定CCR2-64I基因多态性。结果-2518MCP-1、CCR2-64I、SDF1-3'A等位基因及基因型频率在SLE和健康对照组之间差异无显著性。但-2518MCP-1A/G基因型对照组高于病例组(χ2=4.11,P=0.04)。基因间交互作用分析发现,当SDF1-3'A、-2518MCP-1、CCR2-64I基因型分别为G/G、A/G和G/G时,对SLE发病可能具有保护作用(P<0.05)。其他基因型间均未见交互作用(P>0.05)。结论单个-2518MCP-1、CCR2-64I、SDF1-3'A基因多态性与SLE易感性无关联,但他们之间可能存在交互作用。     

Fas promoter -670 polymorphism is associated with development of anti-RNP antibodies in systemic lupus erythematosus

OBJECTIVE: To evaluate whether the polymorphism of Fas promoter -670 is associated with susceptibility to systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA) and their clinical features. METHODS: A polymerase chain reaction of a genomic DNA-restriction fragment length polymorphism was used to determine genotypes of the Fas promoter -670 in 87 patients with SLE, 87 with RA, and 87 healthy controls. A second cohort of SLE patients (n = 85) was included. Clinical manifestations were analyzed in each patient and correlated with the genotypes. RESULTS: The genotype distribution of the Fas promoter -670 did not differ between patients with SLE and control subjects (AA, GA, GG genotypes 31, 54, 15% vs 30, 55, 15% controls, respectively; chi-squared = 0.03, 2 df, p = 0.99) and between RA patients and controls (AA, GA, GG genotypes 38, 44, 18% vs 30, 55, 15% controls, respectively; chi-squared = 2.30, 2 df, p = 0.32). Regarding the clinical status of lupus patients according to Fas promoter -670 genotypes, there was no significant difference in age at onset, anti-dsDNA titer, C3, C4 level, renal involvement, number of American College of Rheumatology (ACR) criteria met, SLE Disease Activity Index, SLE International Collaborating Clinics/ACR Damage Index, or autoantibody profiles. However, the frequency of anti-RNP antibody was significantly different in the AA, GA, and GG groups (71, 25, 30%; chi-squared = 13.29, 2 df, p = 0.001). To confirm this finding, the Fas promoter -670 genotype was examined in a second cohort of SLE patients (n = 85). The result in the second cohort replicated the association shown in the first. In patients with RA, there was no significant difference in clinical and laboratory findings according to the Fas promoter -670 genotypes. CONCLUSION: Our data suggest that the Fas promoter -670 polymorphism is associated with development of anti-RNP antibodies in SLE.     

TNF-308A and HLA-DR3 alleles contribute independently to susceptibility to systemic lupus erythematosus

OBJECTIVE: To evaluate the respective contributions of tumor necrosis factor (TNF) promoter polymorphisms and HLA-DR alleles to susceptibility to systemic lupus erythematosus (SLE). METHODS: TNF-238G/A and 308G/A promoter polymorphisms and HLA-DRB1 alleles were determined in 99 consecutive Caucasian SLE patients and 177 Caucasian controls. Standard and Mantel-Haenszel odds ratios were calculated to assess the magnitude of the susceptibility factors. The presence or absence of the SLE classification criteria was determined and correlated with the TNF promoter and HLA-DRB1 genotypes. RESULTS: The frequency of the TNF-308A/A and 308G/A genotypes was significantly higher in SLE patients (odds ratio 5.0). Conversely, TNF-238G/A and 238A/A genotypes were equally prevalent in SLE patients and controls. The HLA-DR3 specificity (DRBI*0301 allele) was significantly more prevalent in the SLE population (odds ratio 4.4). Stratification to correct for interdependence of the 2 loci confirmed the association of both TNF-308A and HLA-DR3 with SLE (Mantel-Haenszel odds ratio 3.2 and 2.4, respectively). No correlation was found between TNF promoter and HLA-DRB1 genotypes and any SLE classification criterion or disease manifestation. CONCLUSION: TNF-308A and HLA-DR3 alleles are independent susceptibility factors for SLE.     

Interleukin-1 receptor antagonist gene polymorphism and rheumatoid arthritis

The aim of this study was to evaluate the association of polymorphism in IL-1 receptor antagonist (IL-1RA) gene intron 2 with susceptibility to rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE) and their clinical features. Polymerase chain reaction of a genomic DNA was used to determine genotypes of the IL-1RA in 138 RA, 93 SLE, and 127 healthy control subjects. The frequency of IL-1RA allele 2 (IL-1RN*2) was lower in RA patients (2.5%) than in control subjects (7.1%) (odds ratio 0.34, 95% confidence interval 0.13–0.88, P=0.02). There was a significant difference in genotype and allele distribution between RA patients and controls. However, it did not differ between SLE patients and controls. In SLE and RA patients, there was no significant difference in clinical and laboratory findings concerning IL-1RA polymorphisms. In conclusion, our data suggest that IL-1RA gene polymorphism is not responsible for specific clinical characteristics in RA and SLE but that IL-1RN*2 is relevant in the susceptibility to RA, suggesting a protective role of IL-1RN*2 in the pathogenesis of RA.     

系统性红斑狼疮患者白细胞介素-4受体基因多态性的研究

目的初步探讨白细胞介素-4受体(IL-4R)的两个氨基酸位点ile50val和gln576arg多态性与系统性红斑狼疮(SLE)患者发病的相关性。方法采用聚合酶链反应-单链构象多态性(PCR-SSCP)和聚合酶链反应限制性片段多态性(PCR-RFLP)及DNA测序方法进行基因分型。结果ile50/ile50基因型与SLE易感性有显著相关(P=0.022,OR=0.455,95%的可信区间为0.231￣0.897)。其他基因型在两组患者间的分布差异无统计学意义(P>0.1)。各个基因型组合的优势比结果显示ile50/ile50和gln576/arg576两个基因型的组合与SLE的发病易感性显著相关(P=0.056,OR=0.242,95%可信区间为0.051￣1.156)。其他基因型的组合在两组患者间的分布差异无统计学意义(P>0.1)。结论ile50/ile50基因型与SLE易感性有显著相关。ile50/ile50和gln576/arg576两个基因型的组合与SLE的发病易感性显著相关。     

Angiotensin-converting enzyme gene polymorphism in Kuwaiti patients with systemic lupus erythematosus

OBJECTIVE: To investigate the frequency of angiotensin-converting enzyme (ACE) gene insertion/deletion (I/D) polymorphism genotypes in patients with systemic lupus erythematosus (SLE), and to study the correlation between I/D polymorphism of the ACE gene and the clinical manifestations of SLE, especially vascular involvement, lupus nephritis and disease severity. METHODS: The frequency of ACE gene I/D polymorphism genotypes was determined in 92 patients with SLE from Kuwait, and compared to that in 100 ethnically matched healthy controls using the polymerase chain reaction. RESULTS: The distribution of ACE I/D polymorphism and allele frequencies in SLE patients was not significantly different from controls. Further analyses of SLE patients showed that there was a significant association between DD genotype and Raynaud's phenomenon (p=0.008, odd ratio=5.4, 95% confidence interval: 1.6-18.6). However, there was no significant association between the ACE genotype and lupus nephritis or disease severity. CONCLUSION: No difference was found between the distribution of the ACE genotype in SLE patients and the general pop-ulation in Kuwait. However, the presence of the DD genotype may confer susceptibility to the development of vascular morbidity.     

趋化因子CXCL12-3’G801A多态性与系统性红斑狼疮的相关性

目的检测系统性红斑狼疮(systemic lupus erythematosus,SLE)患者趋化因子CXCL12-3’G801A基因型分布,探索该基因变异对SLE的易感性及临床表现、自身抗体生成等的影响。方法用聚合酶链反应-限制性片段长度多态性(PCR-RFLP)方法检测298例中国汉族SLE患者及243名健康对照者的CXCL12-3’G801A基因型,进行Hardy-Weinberg平衡、组间等位基因及基因型频率比较,分析不同基因型SLE患者的临床特征及实验室检查结果。结果 CXCL12-3’801G/G纯合子频率在SLE患者中明显增高(P=0.015),同时携带该基因型的SLE患者易出现光敏感(P=0.014)及肾脏损害(P=0.009),且SLE疾病活动性积分显著增高(P=0.048),抗dsDNA抗体(P=0.004)、抗核小体抗体(P=0.003)阳性率亦明显高于其他基因型患者。结论 CXCL12-3’G801A基因变异参与中国汉族人群SLE疾病易感性过程,并可通过影响自身抗体的生成而影响SLE患者的临床表现及疾病活动性。     

The association between interleukin-6 polymorphisms and systemic lupus erythematosus: a meta-analysis

The aim of this study was to determine whether the functional interleukin-6 (IL-6) promoter -174 G/C and -572 G/C polymorphisms confer susceptibility to systemic lupus erythematosus (SLE) in ethnically different populations. Meta-analysis was conducted on the associations between the IL-6 polymorphisms and SLE using; 1) allele contrast, 2) the recessive model, 3) the dominant model, and 4) the additive model. A total of 11 studies were considered in this study, and ethnicity-specific meta-analysis was performed on European and Asian populations. Meta-analysis of the IL-6 -174 G/C polymorphism showed an association between SLE and the IL-6 -174 G allele in all study subjects (odds ratio (OR)?=?1.344, 95% confidence interval (CI)?=?1.052-1.718, p?=?0.018). Furthermore, stratification by ethnicity indicated an association between the IL-6 -174 G allele and SLE in Europeans (OR?=?1.264, 95% CI?=?1.037-1.541, p?=?0.020). Meta-analysis of the IL-6 -572 G/C polymorphism revealed that an association was found between SLE and the IL-6 -572 G/C polymorphism using the recessive model, but ethnicity-specific meta-analysis revealed no association between SLE and the IL-6 -572 G/C polymorphism in Asians. In conclusion, this meta-analysis demonstrates that the IL-6 -174 G/C polymorphism may confer susceptibility to SLE in Europeans, but that the IL-6 -572 G/C polymorphism is not associated with susceptibility to SLE in Asians.